In the pivotal phase II/III ATOMIC-Meso* trial, adding the first-in-class, arginine-depleting agent pegargiminase to standard first-line platinum-pemetrexed chemotherapy prolongs overall survival (OS) and progression-free survival (PFS) in patients with treatment-naïve, nonresectable, nonepithelioid pleural mesothelioma.
“Both the primary endpoint of OS and secondary endpoint of PFS validate pegargiminase combined with antifolate-based chemo as a novel cancer treatment, in this first (to our knowledge) histologic subtype-driven study of nonepithelioid mesothelioma,” said the researchers. “The pegargiminase group had a 29-percent lower risk of death and a 35-percent lower risk of progression compared with the placebo group.”
Median OS was significantly longer in the pegargiminase vs placebo arm (9.3 vs 7.7 months; stratified hazard ratio [HR] for death, 0.71; p=0.02). One-year OS rates were 41.4 percent and 31.4 percent, respectively. [JAMA Oncol 2024;10:475-483]
“Notably, the survival curves diverged early and remained separate throughout the course of the study. A therapeutic plateau was reached by 36 months with three- to fourfold more patients alive in the pegargiminase vs placebo group (11.9 percent vs 3.3 percent),” the researchers added.
At the time of database lock (August 19, 2022), all participants had a minimum of 12 months’ follow-up for survival. Mortality rates in the pegargiminase and placebo arms were 84 percent and 93.5 percent, respectively.
Median PFS was also markedly longer with pegargiminase-chemo vs placebo-chemo (6.2 vs 5.6 months; stratified HR for disease progression or death, 0.65; p=0.02).
Safety profile
There were more grade ≥3 treatment-emergent adverse events (TEAEs) in the pegargiminase vs placebo arm (28.8 percent vs 16.9 percent; p=0.03). In the pegargiminase arm, three patients reported anaphylactic hypersensitivity, while two had skin reactions; there were none in the placebo arm.
Anaphylactic hypersensitivity occurred with subsequent pegargiminase dosing, usually within cycle 1. According to the researchers, this was managed with steroids, and the experimental drug was either discontinued or administered with hydrocortisone and chlorpheniramine depending on the severity of the anaphylactic reaction.
Of the 19 fatal TEAEs reported (n=7 [pegargiminase] and 12 [placebo]), two were deemed possibly related to pegargiminase (sudden death, sepsis) and one to placebo (sepsis). Discontinuation rates owing to TEAEs were 20 percent and 13.7 percent in the respective pegargiminase and placebo arms.
An incremental chemotherapeutic advance
A total of 249 participants (mean age 69.5 years, 82.7 percent men) were randomized 1:1 to IM pegargiminase 36.8 mg/m2 or placebo weekly, on top of chemo (IV pemetrexed 500 mg/m2 and platinum** Q3W up to six cycles).
The OS benefit seen with nivolumab-ipilimumab (NIVO-IPI) in CheckMate 743 has led to its US FDA approval for mesothelioma in October 2020, thus shifting the mesothelioma treatment landscape in favour of immune checkpoint inhibition. [Lancet 2021;397:375-386; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-and-ipilimumab-unresectable-malignant-pleural-mesothelioma, accessed May 23, 2024]
“While not replacing frontline immunotherapy with the more modest survival improvement in ATOMIC-Meso, pegargiminase nonetheless provides an incremental chemotherapeutic advance for patients with essentially chemo-refractory nonepithelioid disease. Thus, deployment of pegargiminase would be envisaged second-line alongside platinum-pemetrexed,” the researchers said.
A novel therapeutic antimetabolite approach
Of note, enrolment stopped in August 2021 (follow-up until August 2022) owing to the positive results. Factors such as the COVID-19 pandemic and NIVO-IPI approval may have impacted the treatment effect size, the researchers noted. NIVO-IPI use, which was greater in the experimental than the placebo arm (16.8 percent vs 8.9 percent) may have also affected the survival results.
“[Nonetheless,] our novel data add further impetus to the field of cancer metabolism and particularly targeting specific amino acids … The pegargiminase-pemetrexed-platinum triplet … validates arginine deprivation as a novel therapeutic antimetabolite strategy for patients with nonepithelioid mesothelioma,” they said.
They called for further studies looking into the potential of pegargiminase-based regimens in other urea cycle-dysregulated or arginine-dependent cancers with poor survival outcomes.
The findings also support re-evaluation of pemetrexed as maintenance treatment, which has apparently underperformed in mesothelioma. [Clin Lung Cancer 2020;21a:553-561.e1]